Comparative Assessment of the Prognostic Value of Biomarkers in Traumatic Brain Injury Reveals an Independent Role for Serum Levels of Neurofilament Light.

Traumatic brain injury (TBI) is a common cause of death and disability, worldwide. Early determination of injury severity is essential to improve care. Neurofilament light (NF-L) has been introduced as a marker of neuroaxonal injury in neuroinflammatory/-degenerative diseases. In this study we determined the predictive power of serum (s-) and cerebrospinal fluid (CSF-) NF-L levels towards outcome, and explored their potential correlation to diffuse axonal injury (DAI). A total of 182 patients suffering from TBI admitted to the neurointensive care unit at a level 1 trauma center were included. S-NF-L levels were acquired, together with S100B and neuron-specific enolase (NSE). CSF-NF-L was measured in a subcohort (n = 84) with ventriculostomies. Clinical and neuro-radiological parameters, including computerized tomography (CT) and magnetic resonance imaging, were included in the analyses. Outcome was assessed 6 to 12 months after injury using the Glasgow Outcome Score (1-5). In univariate proportional odds analyses mean s-NF-L, -S100B and -NSE levels presented a pseudo-R2 Nagelkerke of 0.062, 0.214 and 0.074 in correlation to outcome, respectively. In a multivariate analysis, in addition to a model including core parameters (pseudo-R2 0.33 towards outcome; Age, Glasgow Coma Scale, pupil response, Stockholm CT score, abbreviated injury severity score, S100B), S-NF-L yielded an extra 0.023 pseudo-R2 and a significantly better model (p = 0.006) No correlation between DAI or CT assessed-intracranial damage and NF-L was found. Our study thus demonstrates that S-NF-L correlates to TBI outcome, even if used in models with S100B, indicating an independent contribution to the prediction, perhaps by reflecting different pathophysiological processes, not possible to monitor using conventional neuroradiology. Although we did not find a predictive value of NF-L for DAI, this cannot be completely excluded. We suggest further studies, with volume quantification of axonal injury, and a prolonged sampling time, in order to better determine the connection between NF-L and DAI.

Intermittent versus continuous cerebrospinal fluid drainage management in adult severe traumatic brain injury: assessment of intracranial pressure burden.

INTRODUCTION: There is clinical equipoise regarding whether neurointensive care unit management of external ventricular drains (EVD) in severe traumatic brain injury (TBI) should involve an open EVD, with continuous drainage of cerebrospinal fluid (CSF), versus a closed EVD, with intermittent opening as necessary to drain CSF. In a matched cohort design, we assessed the relative impact of continuous versus intermittent CSF drainage on intracranial pressure in the management of adult severe TBI. METHODS: Sixty-two severe TBI patients were assessed. Thirty-one patients managed by open EVD drainage were matched by age, sex, and injury severity (initial Glasgow Coma Scale (GCS) score) to 31 patients treated with a closed EVD drainage. Patients in the open EVD group also had a parenchymal intracranial pressure (ICP) monitor placed through an adjacent burr hole, allowing real-time recording of ICP. Hourly ICP and other pertinent data, such as length of stay in intensive care unit (LOS-ICU), Injury Severity Score, and survival status, were extracted from our prospective database. RESULTS: With age, injury severity (initial GCS score), and neurosurgical intervention adjusted for, there was a statistically significant difference of 5.66 mmHg in mean ICP (p < 0.0001) between the open and the closed EVD groups, with the closed EVD group exhibiting greater mean ICP. ICP burden (ICP ≥ 20 mmHg) was shown to be significantly higher in the intermittent EVD group (p = 0.0002) in comparison with the continuous EVD group. CONCLUSION: Continuous CSF drainage via an open EVD seemed to be associated with more effective ICP control in the management of adult severe TBI.

A non-invasive assessment of intracranial volume reserve by measuring cerebrospinal fluid volume with the aid of CT imaging.

INTRODUCTION: Monitoring changes in the intracranial volume (ICV) reserve and intracranial pressure (ICP) is one of the key issues in the treatment of intracranial pathologies. The aim of this study is to develop a method of monitoring the ICV reserve by analyzing CSF volume measured using CT in specific regions. MATERIALS AND METHODS: A total of 20 patients with cerebral injury were evaluated. Analysis was performed using imaging software. On selected scans (three at the basal cistern level and three at the pineal level), the following regions were analyzed: total cerebral surface (TC1, TC2) and bilateral ambient cistern (AC) only at the basal cistern level for cerebrospinal fluid (CSF) volume. Results were correlated with patients' Glasgow Coma Scale (GCS) scores. RESULTS: An increase of CSF volume was observed with an improvement in the GCS. From the examined regions, only AC volume showed a statistically significant linear correlation (p < 0.0005) with GCS. Mean AC: 0.021, 0.454, and 0.678 mL CSF/scan in severe (3-8 pts GCS), moderate (9-12 pts GCS), and mild (13-15 pts GCS) TBI groups, respectively. DISCUSSION: Assessment of CSF volume changes in mL CSF/scan can be conducted using CT. Counting voxels corresponding to the CSF eliminates mistakes due to inaccurate region demarcation. The obtained results (AC volume) show a high correlation with patient state.

Multiplex assessment of cytokine and chemokine levels in cerebrospinal fluid following severe pediatric traumatic brain injury: effects of moderate hypothermia.

This study performed a comprehensive analysis of cerebrospinal fluid (CSF) cytokine levels after severe traumatic brain injury (TBI) in children using a multiplex bead array assay and to evaluate the effects of moderate hypothermia on cytokine levels. To this end, samples were collected during two prospective randomized controlled trials of therapeutic moderate hypothermia in pediatric TBI. Thirty-six children with severe TBI (Glasgow Coma Scale [GCS] score of

Assessment of the macrophage marker quinolinic acid in cerebrospinal fluid after pediatric traumatic brain injury: insight into the timing and severity of injury in child abuse.

This study measured quinolinic acid (QUIN), a macrophage-microglia derived neurotoxin, in the cerebrospinal fluid (CSF) of children after non-inflicted and inflicted traumatic brain injury (nTBI, iTBI), and correlated QUIN concentrations with age, mechanism of injury (nTBi vs. iTBI), Glasgow Coma Scale (GCS) score and 6-month Glasgow Outcome Score. One hundred fifty-two CSF samples were collected from 51 children with severe TBI (GCS < or = 8). CSF was collected at the time an intraventricular catheter was placed and daily thereafter. QUIN concentration was measured by gas chromatography-mass spectroscopy. Patients ranged in age from 2 months to 16 years. Eleven children (22%) had iTBI. Initial and peak CSF QUIN concentrations were higher in patients with iTBI versus nTBI after adjusting for time after injury and GCS. Despite the lack of a history of trauma in 82% of children with iTBI, 100% had a peak QUIN concentration of >100 nM. There was a significant increase in the CSF concentrations of QUIN following severe nTBI and iTBI in children. Higher initial and peak QUIN concentrations after iTBI may be due to severity of injury, young age, and/or delay in seeking medical care, which allows for increased secondary injury.

Assessment of antioxidant reserves and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children.

Studies in experimental traumatic brain injury (TBI) support a key role for oxidative stress. The degree of oxidative injury in clinical TBI, however, remains to be defined. We assessed antioxidant defenses and oxidative stress in pediatric TBI by applying a comprehensive battery of assays to cerebrospinal fluid samples. Using a protocol approved by our institutional review board, 87 cerebrospinal fluid samples from 11 infants and children with severe TBI (Glasgow Coma Scale score < or = 8) and 8 controls were studied. Cerebrospinal fluid was drained as standard care after TBI. CSF was assessed on d 1, 2, and 5-7 after ventricular drain placement. Biochemical markers of oxidative stress included F(2)-isoprostane and protein sulfhydryl (detected by ELISA and fluorescence assay, respectively). Antioxidant defenses were measured by determination of total antioxidant reserve (via chemiluminescence assay), and ascorbate (via HPLC) and glutathione (via fluorescence assay) concentrations. Free radical production (ascorbate radical) was assessed by electron paramagnetic resonance spectroscopy. F(2)-isoprostane was markedly increased versus control, maximal on d 1 (93.8 +/- 30.8 pg/mL versus 7.6 +/- 5.1 pg/mL, p < 0.05). Total antioxidant reserve was reduced versus control. Reduction was maximal on d 5-7 (81.8 +/- 3.7 microM versus 178.9 +/- 2.2 microM, p < 0.05). Ascorbate was remarkably reduced (53.8 +/- 8 microM versus 163.8 +/- 21 microM on d 1, p < 0.05). Ascorbate depletion was likely associated with its free radical oxidation, as evidenced by electron paramagnetic resonance spectroscopy. Glutathione levels increased on d 1, then decreased versus control (0.19 +/- 0.05 microM versus 1.2 +/- 0.16 microM, p < 0.05). This is the first comprehensive study of antioxidant reserve and oxidative injury in clinical TBI. Progressive compromise of antioxidant defenses and evidence of free radical-mediated lipid peroxidation are noted. These markers could be used to monitor antioxidant strategies in clinical trials.

"Extrapolated" creatine kinase-BB isoenzyme activity in assessment of initial brain damage after severe head injury.

The severity of initial brain damage is an important risk factor in determining the prognosis of head trauma. It can be assessed by assigning neurological scores or by determining the cerebrospinal fluid (CSF) activity of the isoenzyme creatine kinase-BB (CK-BB). In 10 severely head-injured patients serial CSF samples were obtained during the first 24 hours after trauma, and exponential decay of CK-BB activity with an average half-life of 4.5 hours was demonstrated. This finding led the authors to propose an "extrapolated" CK-BB activity, which theoretically occurs immediately after injury and is calculated from a single CK-BB recording, as a new index for assessing the degree of initial brain damage. In 50 patients with severe head injury, the prognostic ability of "observed" and "extrapolated" CK-BB activity was compared with two clinical scoring systems that evaluate severity of head trauma (the Glasgow and the Glasgow-Liège Coma Scales). "Extrapolated" CK-BB activity proved to be the best prognostic factor. With a CK-BB cutoff point of 330 U/liter, a true-positive rate of 79% and a true-negative rate of 73% were obtained. These results suggest the usefulness of measuring CK-BB activity in CSF as soon as possible after hospital admission for head injury.